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PubMed2000

Comparison of allele-sharing statistics for general pedigrees.

The popularity of "non-parametric" linkage analysis using moderate and large sized pedigrees has increased in the last few years. Only a few of the existing allele-sharing statistics are applicable to general pedigrees, and even fewer are in common use. Little research has been done to compare the power of these statistics. We present some preliminary investigations into the power of the most popular general-pedigree allele-sharing statistics. We show that there are indeed non-trivial differences among the statistics, and that further studies are warranted. In particular, pedigree structure and the degree of recessiveness of the trait appear to be critical factors in determining which statistics are most powerful.

Alleles↗
PubMed1999

Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees.

Restless legs syndrome (RLS) can occur with an autosomal-dominant mode of inheritance. To determine if there are distinguishing features of RLS pedigrees which might clarify molecular mechanisms of pathogenesis, five pedigrees with 81 affected members were analyzed for age of onset, sex ratio, and transmission pattern. One-factor analysis of variance of ages of onset between generations was carried out, and segregation ratios were calculated for each generation. These kindreds showed an autosomal-dominant mode of inheritance and a male:female ratio of 1:1.4 (p = 0.15). One of the five analyzed pedigrees shows some evidence of reduced penetrance. In two of the five analyzed pedigrees, there is statistical support for anticipation (p<0.05). These variations in penetrance and anticipation suggest possible genetic heterogeneity.

Adolescent↗
PubMed1999

Multicenter study of paroxysmal dyskinesias in Japan--clinical and pedigree analysis.

To investigate the clinical features of paroxysmal dyskinesias and carry out a pedigree analysis, we conducted a multicenter survey in Japan. A questionnaire was mailed to 229 medical institutions. A total of 150 patients with paroxysmal kinesigenic choreoathetosis (PKC), including 53 sporadic cases and 97 affected individuals from 32 pedigrees, were identified. The mean age of onset of PKC was 8.8 years, and 80% of the cases were men. Of the 32 pedigrees with familial occurrence, 18 (56%) were compatible with an autosomal-dominant inheritance (AD) with complete penetrance, and seven (22%) had AD with incomplete penetrance; the remaining seven were sibling recurrence cases with apparently healthy parents. In six of seven familial cases with incomplete penetrance, the disease gene was thought to be transmitted by clinically unaffected females. Paroxysmal dystonic choreoathetosis (PDC) was found in five cases, including two sporadic cases and three affected individuals from two pedigrees; the mean age of onset was 0.6 years, and a male predominance was noted (male:female = 4:1). There was one case of paroxysmal hypnogenic dyskinesia and one case of paroxysmal exertion-induced dyskinesia. There is an unexplained male predominance for paroxysmal dyskinesias. When the genetic defect of patients with paroxysmal dyskinesias is identified, the pathophysiology of the disease will become more clear.

Adolescent↗
PubMed1980

Discriminating among single locus models using small pedigrees.

Simulated small pedigrees (2 parents, 4 offspring) were used to illustrate the applications and limitations of a "model choice" approach designed to detect genetic heterogeneity in familial diseases. While it is possible to identify groups of pedigrees which have different genetic causes for quanitative phenotypic trait(s), theoretical limitations on discriminating between 4 single locus models exist for certain pedigree structures. These limitations originate from the overlapping phenotypic predictions of the various genetic models. Such limitations must be carefully considered in the design of genetic studies. Studies aimed at detecting genetic heterogeneity in familial diseases should limit the different genetic models being considered and tailor the sampling strategy to avoid collecting pedigrees which are non-informative for certain comparisons.

Alleles↗
PubMed1983

Pedigree discriminant analysis: a method to identify monogenic segregation.

We describe a method for obtaining a linear discriminant function to identify monogenic segregation in multivariate pedigree data. It differs from Fisher's linear discriminant function in that it does not assume that the genotype of each individual in the pedigree already known. The method consists of finding that linear function of the variables that maximizes the likelihood of a set of pedigree data, under the hypothesis of single gene segregation, subject to the constraint that the total sample variance of the function remains constant. To simplify the computation the variables are first transformed to their standardized principal components. Reanalysis of a set of pedigree data suggests that age and powers of age should be considered as extra variables from which the principal components are obtained, and virtually all of the variance should be accounted for by the principal components used to obtain the discriminant function.

Age Factors↗
PubMed1986

A re-examination of major locus hypotheses for high density lipoprotein cholesterol level using 2,170 persons screened in 55 Utah pedigrees.

A dominant major locus (allele frequency of .0025 +/- .0014), resulting in low levels of high density lipoprotein cholesterol (HDL-C), was revealed by likelihood analysis on 2,170 persons in 55 Utah pedigrees. This allele was expressed through HDL-C levels ranging from 20 to 30 mg/dl in seven persons in two pedigrees. Early coronary heart disease was associated with the allele in one pedigree, but not in the other. In the pedigree without associated heart disease, HDL subfractions HDL2 and HDL3 were both low in individuals with the low HDL-C allele. No other major locus determining either high or low levels of HDL-C was identified in our sample. Polygenic heritability as part of the mixed model was estimated as .561 +/- .035.

Adolescent↗
PubMed2001

Multipoint development of the weighted pairwise correlation (WPC) linkage method for pedigrees of arbitrary size and application to the analysis of breast cancer and alcoholism familial data.

The weighted pairwise correlation (WPC) method is a simple and powerful model-free method of linkage analysis that has the advantages of being applicable to binary, ordered categorical, quantitative, or censored traits, and to consider all pairs of relatives in large pedigrees. The originally implemented approach was limited to the use of the identical by state (IBS) information, and we recently extended the WPC method to incorporate the identical by descent (IBD) information for two-point linkage analysis. Here, we develop a multipoint WPC method suitable for pedigrees of arbitrary size and large number of markers. The multipoint IBD estimation procedure for relative pairs is based on the efficient regression approach developed for pedigrees implemented in SOLAR. A robust and fast Monte-Carlo procedure is used to determine reliable P values. Application of the method to the 214 pedigrees from the Breast Cancer Linkage Consortium provided for the Genetic Analysis Workshop (GAW) 9 shows that multipoint WPC statistic values were not far from two-point maximum lod-score values obtained by the classical parametric linkage method and were higher than multipoint variance component analysis lod-scores obtained with SOLAR. The multipoint WPC method is also used to analyze the familial Collaborative Study of the Genetics of Alcoholism data on alcoholism released for GAW11. It allows a better specification of the linkage results previously obtained within the chromosome 4 region.

Alcoholism↗
PubMed2003

Finding starting points for Markov chain Monte Carlo analysis of genetic data from large and complex pedigrees.

Genetic data from founder populations are advantageous for studies of complex traits that are often plagued by the problem of genetic heterogeneity. However, the desire to analyze large and complex pedigrees that often arise from such populations, coupled with the need to handle many linked and highly polymorphic loci simultaneously, poses challenges to current standard approaches. A viable alternative to solving such problems is via Markov chain Monte Carlo (MCMC) procedures, where a Markov chain, defined on the state space of a latent variable (e.g., genotypic configuration or inheritance vector), is constructed. However, finding starting points for the Markov chains is a difficult problem when the pedigree is not single-locus peelable; methods proposed in the literature have not yielded completely satisfactory solutions. We propose a generalization of the heated Gibbs sampler with relaxed penetrances (HGRP) of Lin et al., ([1993] IMA J. Math. Appl. Med. Biol. 10:1-17) to search for starting points. HGRP guarantees that a starting point will be found if there is no error in the data, but the chain usually needs to be run for a long time if the pedigree is extremely large and complex. By introducing a forcing step, the current algorithm substantially reduces the state space, and hence effectively speeds up the process of finding a starting point. Our algorithm also has a built-in preprocessing procedure for Mendelian error detection. The algorithm has been applied to both simulated and real data on two large and complex Hutterite pedigrees under many settings, and good results are obtained. The algorithm has been implemented in a user-friendly package called START.

Algorithms↗
PubMed2001

The importance of connections: joining components of the Hutterite pedigree.

We analyzed a quantitative trait (serum IgE levels), and a binary trait (asthma), in four Hutterite sub-pedigrees. A genome screen for asthma was performed using GENEHUNTER, and interesting regions were followed up using extended pedigrees and the FASTLINK package. Markov chain Monte Carlo (MCMC) methods were used to assess haplotype sharing among affected individuals (MORGAN/AUTOZYG), and to perform a combined oligogenic segregation and linkage analysis (LOKI) for log10(IgE). We found evidence for at least two susceptibility loci for asthma on chromosome 5, and a QTL for log10(IgE) on chromosome 1. Our analyses demonstrate that using the most complete pedigree structure possible is advisable, with attention to the possibility of heterogeneity among subunits of a very large pedigree.

Adult↗
PubMed2005

Case-control single-marker and haplotypic association analysis of pedigree data.

Related individuals collected for use in linkage studies may be used in case-control linkage disequilibrium analysis, provided one takes into account correlations between individuals due to identity-by-descent (IBD) sharing. We account for these correlations by calculating a weight for each individual. The weights are used in constructing a composite likelihood, which is maximized iteratively to form likelihood ratio tests for single-marker and haplotypic associations. The method scales well with increasing pedigree size and complexity, and is applicable to both autosomal and X chromosomes. We apply the approach to an analysis of association between type 2 diabetes and single-nucleotide polymorphism markers in the PPAR-gamma gene. Simulated data are used to check validity of the test and examine power. Analysis of related cases has better power than analysis of population-based cases because of the increased frequencies of disease-susceptibility alleles in pedigrees with multiple cases compared to the frequencies of these alleles in population-based cases. Also, utilizing all cases in a pedigree rather than just one per pedigree improves power by increasing the effective sample size. We demonstrate that our method has power at least as great as that of several competing methods, while offering advantages in the ability to handle missing data and perform haplotypic analysis.

Alleles↗
PubMedDate not supplied

Comparison of ascertainment-bias correction schemes for pedigrees ascertained through multiple probands.

Assessing the genetic causation of a disease, which is of prime importance in medical genetics, is usually done by analysing pedigree data. When gathering such data, it is often more practical to adopt a non-random sampling strategy. However, unless suitable corrections for non-random sampling are made at the time of data analysis, inferences may be grossly affected. For pedigree data ascertained through multiple probands, various correction schemes have been suggested, although the efficiencies of these schemes are unknown. This paper compares such schemes, using Monte Carlo simulation techniques, under a simple genetic model, for pedigrees of fixed sizes and structures and for probands of two types of relationship--parent-offspring, and a pair of siblings. It is found that gene frequencies are grossly overestimated and the penetrance value of heterozygotes slightly underestimated whether or not any correction for non-random sampling of pedigrees is made. Knowledge of the population value of the gene frequency improves the estimate of the penetrance parameter.

Biometry↗
PubMed1990

Biochemical genetic markers of squirrel monkeys and their use for pedigree validation.

Family data for 14 biochemical genetic markers fo squirrel monkeys (genus Saimiri) were derived from 73 pedigreed progeny and both parents of each, as well as from 16 additional progeny and one parent of each. The data for each marker and the phenotypic patterns were consistent with autosomal codominant inheritance. It was concluded from the genetic marker data that the pedigree records of seven progeny were incorrect. Retrospective investigations of colony records followed by typing of animals that might possibly have been a parent enabled five of the pedigree records to be corrected. Although five of the pedigree errors were cases of mistaken paternity, the other two apparently were the consequence of infant swapping between dams shortly after birth. Because squirrel monkeys exhibit a high degree of allomaternal behavior, infant swapping between dams may occur more frequently than in many other nonhuman primate species.

Alleles↗
PubMed2003

RAPD and pedigree-based genetic diversity estimates in cultivated diploid potato hybrids.

In this study, RAPD and pedigree data were used to investigate the genetic relationships in a group of 45 diploid hybrid potato clones used in the breeding and genetics program of the Agriculture and Agri-Food Canada Potato Research Centre in Fredericton, New Brunswick, and used for the potato after-cooking darkness program at the Nova Scotia Agricultural College. These hybrids were derived from crossing primitive cultivated South American diploid species such as Solanum phureja or Solanum stenotomum and wild diploid species such as Solanum chacoense and other wild Argentine species with haploids of Solanum tuberosum. These hybrids have subsequently undergone up to 30 years of breeding and selection, for adaptation to local growing and storage conditions, processing traits and pest resistances. The objectives of this study were to estimate the level of genetic similarity (GS) among these sets of clones and to investigate the correlation between RAPD-based GS and f, based on pedigree information. Genetic similarity coefficients varied from 0.29 to 0.90 with a mean of 0.65 when based on the RAPD data, whereas the coefficient of parentage varied from zero to 0.75 with a mean of 0.11. The degree of relationship between the similarity matrices based on RAPD and pedigree was measured by comparing the similarity matrices with the normalized Mantel test. A low positive correlation (R = 0.104, p = 0.999) between the two matrices was observed. Cluster analysis using GS divided the clones into many subgroups that did not correspond well with the grouping based on pedigree. The level of genetic variation present in this set of potato clones is very high. Rigorous selection pressure aimed at different breeding purposes may result in the genetic differentiation of the clones from the same origin.

DNA, Plant↗
PubMed2006

Identification of genetic loci for basal cell nevus syndrome and inflammatory bowel disease in a single large pedigree.

Basal Cell Nevus Syndrome (BCNS) is an autosomal dominant disease. PTCH1 gene mutations have been found responsible in many but not all pedigrees. Inflammatory Bowel Disease (IBD) is a complex genetic disorder, disproportionate in Ashkenazim, and characterized by chronic intestinal inflammation. We revisited a large Ashkenazim pedigree, first reported in 1968, with multiple diagnoses of BCNS and IBD, and with a common genetic cause for both disorders proposed. We expanded the pedigree to four generations and performed a genome-wide linkage study for BCNS and IBD traits. Twelve members with BCNS, seven with IBD, five with both diagnoses and eight unaffected were genotyped. Both non-parametric (GENEHUNTER 2.1) and parametric (FASTLINK) linkage analyses were performed and a validation through simulation was performed. BCNS linked to chromosome 9q22 (D9S1120) just proximal to the PTCH1 gene (NPL=3.26, P=0.003; parametric two-point LOD=2.4, parametric multipoint LOD=3.7). Novel IBD linkage evidence was observed at chromosome 1p13 (D1S420, NPL 3.92, P=0.0047; parametric two-point LOD=1.9). Linkage evidence was also observed to previously reported IBD loci on 4q, (D4S2623, NPL 3.02, P=0.012; parametric two-point LOD=2.15), 10q23 (D10S1225 near DLG5, NPL 3.33, P=0.0085; parametric two-point LOD=1.3), 12 overlapping the IBD2 locus (D12S313, NPL 2.6, P=0.018; parametric two-point LOD=1.52), and 7q (D7S510 and D7S3046, NPL 4.06, P=0.0035; parametric two-point LOD=2.18). In this pedigree affected by both BCNS and IBD, the two traits and their respective candidate genetic loci segregate independently; BCNS maps to the PTCH1 gene and IBD maps to several candidate regions, mostly overlapping previously observed IBD loci.

Basal Cell Nevus Syndrome↗
PubMed2006

Ala45Thr variation in neuroD1 gene is associated with early-onset type 2 diabetes with or without diabetic pedigree in Chinese.

OBJECTIVE: Based on onset-age stratified analysis may be useful to determine the association of NeuroD1-Ala45Thr variation with susceptibility to genetic heterogeneous type 2 diabetes mellitus (T2DM), we investigated the Ala45Thr variation in unrelated early-onset and late-onset T2DM with or without diabetic pedigree and unrelated non-diabetic control subjects in Chinese. METHODS: 175 early-onset and 194 late-onset type 2 diabetic patients were further divided into two subgroups according to with or without diabetic pedigree respectively. This NeuroD1-Ala45Thr variation were screened by PCR-direct sequencing in above 369 type 2 diabetic patients and 87 unrelated non-diabetic control subjects. We then compared the distribution of the Ala45Thr variation among the groups, searching for the predictive trends. RESULTS: Frequencies of the variant (AA + GA genotype) in early-onset T2DM are obviously elevated, especially among diabetic pedigree subjects when compared to non-diabetic controls (p= 0.003) and late-onset T2DM subjects (p = 0.014). However, no significant differences were observed between late-onset T2DM with or without diabetic pedigree and non-diabetic control subjects. CONCLUSIONS: Our results suggest that 1) the NeuroD1-Ala45Thr variation may itself have an important role in susceptibility to or be in disequilibrium with early-onset T2DM in Chinese; 2) the Ala45Thr may affect the onset pattern of T2DM, i.e., early-onset but not late-onset T2DM in Chinese; and 3) onset-age stratified analysis may be useful to determine the association of NeuroD1-Ala45Thr variation with susceptibility to genetic heterogeneous T2DM in Chinese.

Adult↗
PubMed2005

Absence of linkage to 8q23.3-q24.1 and 2p11.1-q12.2 in a new BAFME pedigree in China: indication of a third locus for BAFME.

Benign adult familial myoclonic epilepsy (BAFME) were mapped on chromosome 8q24 and 8q23.3-q24.1 in Japanese pedigrees and mapped on 2p11.1-2q12.2 in European pedigrees, respectively. Recently, we recruited a large BAFME pedigree in China. After genotyping 11 microsatellite markers covering the two previously identified chromosome regions, we performed linkage analyses. However, evidence of negative linkage was found in the two previously reported candidate regions (LOD score <-3.0 at no recombination). Our data suggest that the causative gene responsible for BAFME in the Chinese pedigree may be located on a new region other than 8q23.3-q24.1 and 2p11.1-q12.2, indicating the presence of a third locus for BAFME.

Adult↗
PubMed2005

Thinking within the spectrum: schizophrenic thought disorder in six Danish pedigrees.

Formal thought disorder (FTD), a major symptom of schizophrenia, is known to aggregate in families. Our aim was to examine the specificity of FTD in the schizophrenia spectrum disorders and the hypothesized linear aggregation of FTD within pedigrees. Six individuals with a diagnosis of schizophrenia were identified in the Copenhagen High-Risk study and each pedigree was centered on one of the six original schizophrenic probands' nuclear families. The 329 pedigree members in the study were considered at risk for schizophrenia spectrum disorders because most were genetically related to the originating schizophrenic probands. The participants were administered the Copenhagen Interview of Functional Illness to determine diagnoses and the Thought Disorder Index (TDI) was used to assess FTD. Individuals with a schizophrenia diagnosis had higher global levels of FTD, exhibited more severe types of FTD, and had a qualitatively different type of FTD than did participants with other diagnoses or no mental illness. Individuals with Cluster A diagnoses exhibited more FTD and FTD similar in quality to participants with schizophrenia. These results support the construct of a spectrum of schizophrenia conditions. There was a generally high level of FTD in the pedigrees, in part due to assortative mating in this sample. However, there was no apparent pattern of linear aggregation of FTD within the families.

Adolescent↗
PubMed1991

The clinical characteristics of pedigrees of Leber's hereditary optic neuropathy with the 11778 mutation.

In a study of the phenotypic characteristics of pedigrees of Leber's hereditary optic neuropathy positive for the mitochondrial DNA mutation at position 11778, 28 of 49 pedigrees were represented by singleton cases. Seven families, including six singleton pedigrees, had maternal family members with a mixture of mutant and normal mitochondrial DNA (heteroplasmy). Seventy-two affected individuals from 43 families showed a male predominance of 81.9% (59/72) and ages of onset of visual loss ranging from 8 to 60 years. The time interval between affected eyes averaged 1.8 months; the duration of progression of visual loss in each eye averaged 3.7 months. Visual acuity was 20/200 or worse in 107 of 109 (98.2%) eyes. Telangiectatic microangiopathy, disk pseudoedema, or vascular tortuosity, ophthalmoscopic features believed to be classic of Leber's hereditary optic neuropathy, were noted in 30 of 52 patients. Visual-evoked responses were typically absent or abnormal. Electrocardiograms, fluorescein angiograms, cerebrospinal fluid analyses, brain computed tomography, and magnetic resonance imaging were usually normal. There were no consistent neurologic or systemic illnesses associated with these Leber's pedigrees. In many cases, the diagnosis would not have been suspected because of the absence of a compatible family history, typical clinical profile, or ophthalmoscopic appearance. Genetic analysis showed the mitochondrial DNA mutation at position 11778, which established the diagnosis of Leber's hereditary optic neuropathy and has allowed for a broader view of the clinical features of this disease.

Adolescent↗